Manufacture of z



Patented Jan. 3, i950 MANUFACTURE OF 2.7 -DIAMINOACRIDONE Alan August Goldberg and William Kelly, Bradford-on-Avon, England, assignors to Ward,

Blenkinsop & Company Limited, Liverpool, England, a British company No Drawing. Application March 8, 1946, Serial No. 653,162. In Great Britain March 12, 1945 9 Claims. (Cl. 260-279) This invention relates to a new and improved process for the manufacture of 2.7-disubstituted acridones in which the substituents each contain a nitrogen atom directly linked to a nuclear proceed, to a major extent, in a different manner, 1. e. the ring closure takes place on to the 6'- position thereby yielding a derivative of 2-aminoacridone.

The group R in the general substituents in an Such reduction can readily carbon atom. Among such acridones is the 5 The group R in the above general formula valuable 2.7-diaminoacridone having the formula may be an amino group, a substituted amino group, such as a monoalkyl or dialkylamino group, it a protected amino group, such as an acylamino EN 4 3 group or a nitro, nitroso, azo, hydrazo or hydroxylamino group. 10 formula may be an amino group, a substituted N 1 'amino group, a protected amino group or an azo, Q hydrazo or hydroxylamino group. (according to the nomenclature of the Chemical g g gmploygf may 2 or Society of London) from which the pharmaconcen m 6 or may av? Ben colo ically valuable 2 7-diaminoacridine can be .dlluted to some extent Wlth water obtained be employed alone or together w1th additlonal The process according to the present invention Substance? Sue}? as phosphoric amd and/0r anhyfor the production of a 2 7-substituted acridone drous? Preferably 9Oncent-rated Sulcomprises heating a 3 '-disubstituted diphenylphunc mm 15 employed Heatmg penods of the b n f th ener 1 f m 1 order of 1 to 2 hours at 100 C. have been found amme car oxy 0 ac o e g a or u a to be sufiicient with concentrated acid. Some- COOH what longer times should be employed at lower 3 2 temperatures and correspondingly shorter times at higher temperatures if these are employed. In

- general we prefer to avoid the use of substanin wh ch R is a amino p, a Substituted tlally higher temperatures on account of secondamino gI'OLlp, a! protected amlIlO group 01 2: nitro, ary reactions may ccur nitroso, azo, hydrazo hydroxylamino group and It has been found that when one or both of the R is an amino group, a substituted amino group, :39 groups 1 and 2 is or are an acylamino group a protected amino p E11 ELZO, hydmZO or groups the cyclisation of the diphenylaminehydroXy a o o p, With Sulphuric afiid- '2-carboxylic acid is usually accompanied by The nventio includes a p o ess for the .simultaneous deacylation. Examples of simulta- Dmduction 0f 2-7-diamin0aCrid01l-e which neous deacylation and ring closure are the action prises heating a 3'z4-disubstituted diphenyl- 33 of hot sulphuric acid upon the 3-amino-4-acylamine-Z-carboxylic acid of the general formula amino-diphenylamine2carboxylic acid, for set forth above in which R and R are amino ample 3-amino-4-acetylamino-diphenylami and/or acylamino groups, with sulphuric acid. Z-carboxylic acid, to give 2.7-diaminoacridone, Preferably the diphenylamine-Z-carboxylic acid and upon 3-aminoand the 3'-acylamino-4- employed is a 3'-aminol-acy1amin0-diphenyl- 40 nitrodiphenylamine-2-carboxylic acids, for exmin -car oxyl id suc a 3-amin0-4- ample 3-acetylamino-l-nitro-diphenylamine-2- y p y arboXylic acid. carboxylic acid, to give 2-amino-'Y-nitroacridone. The invention also includes a process for the When the group R is a nitro, nitroso, azo, production of 2-amino-7-nitroacridone which hydrazo or hydroxylamino group and/or the group comprises heating a 3-aminoor 3'-acylamino- R is an azo, hydrazo or hydroxylamino group, 4-nitrodiphenylamine-2-carboxylic acid with sulthe resulting acridones containing these groups Dhuric acidas substituents may be readily reduced to free It is known that the cyclisation of 3"-nitro amino groups by the use of any of the known diphenylamine-z-carboxylic a yields 4-I1itr0- agents for the reduction of such groups to amino acridone, i. e. ring closure takes place on to the groups when present as 2-position. It is therefore the more surprising aromatic nucleus. that when the 3'-nitro group is replaced by an be carried out by the use of tin and an excess amino group, a substituted amino group, a proof hydrochloric acid or preferably by the use of tected amino group or an azo, hydrazo or stannous chloride dissolved in hydrochloric acid. hydroxylamino group the ring closure should For example, 2-amino-7-nitroacridone can be 3 readily reduced by stannous chloride dissolved in hydrochloric acid to 2.7-diaminoacridone. The reduction is preferably carried out in the warm, temperatures of 80 to 90 C. being very suitable. The acridone is added portionwise to the reducing solution so as to maintain the temperature within the desired range. The resulting stannichloride is decomposed with aqueous alkali and the resulting 2.7-diaminoacridone purified. The reduction may be carried out substantially as described in Example 3 of copending application of Alan August Goldberg, Serial No. 647,187, for Improvement in process for the production of 2.7-dinitroacridone with suitable adjustment of the amount of starting material having due regard for the fact that there is only one nitro group to be reduced in 2-amino-7-nitroacridone.

The 2.7-diaminoacridone may then, in turn, be reduced to 2.7-diaminoacridine. This is preferably carried out using an alkali metal amalgam, such .as sodium amalgam, in neutral or slightly alkaline solution. Reduction to the corresponding acridane occurs in this process and it is necessary to reoxidize to the acridine. This maybe carried out by passing a stream of oxygen or air into a stirred suspension of the acridane preferably in the presence of a ferric salt, such as ferric chloride; preferably this reoxidation is carried out at a temperature somewhat above room temperature, i. e. at about 50-70 0., preferably about 60 C. The production of 2.7- diaminoacridine .from 2.7-diaminoacridone by this process is described in detail in Example 4 of the aforesaid copending application Serial No. 647,187.

The thus produced 2.7-diaminoacridine can be readily converted into the monohydrochloride by suspending the compound in hot Water, adding the theoretical amount of hydrochloric acid to convert to the monohydrochloride and salting out the resulting salt by the addition of a salting out solution of an alkali chloride, such as sodium or ammonium chloride. This procedure also is described in detail in Example 4 of copending application Serial No. 647,187.

It is found that good yields of 2.7-disubstituted acridones, especially 2-amino-7-nitroacridone and 2.7-diaminoacridone can be obtained by the cyclization procedure described and the products need little, if any, purification when used in the production of 2.7-diaminoacridine.

The following examples illustrate the manner in which the invention may be carried into efiect.

Example 1 60 parts of 3'-amino-4-acetylamino-diphenylamine-Z-carboxylic acid is added to 773 parts of concentrated sulphuric acid and the mixture heated for 2 hours at 100 C. The reaction mixture is then cooled, 200 parts of water is added and it is then heated again for a further 30 minutes at 100 C. The mixture is then basified with ammonia whereupon 40 parts of crude 2.7-diaminoacridone is obtained. Upon recrystallization from aqueous pyridine the 2.7-diaminoacridone is obtained pure, in the form of brown crystals, having a melting point of 350-352 0.

Example 2 35 parts of 3-amino-4-nitrodipheny1amine-2- carboxylic acid is heated with 480 parts of sulphuric acid at 100 C. for 1 hours and the solution poured on to an excess of crushed ice. The insoluble material is filtered ofi, stirred with an excess of dilute aqueous ammonia and the crude 4 2-amino-7-nitroacridone (30 parts) collected. Reduction of this with stannous chloride and hydrochloric acid in known manner yields 2:7-diaminoacridone in excellent yield as a yellow brown powder M. Pt. 350--352 C.

The .3' -amino-4-nitro-diphenylamine-2 carboxylic acid employed is conveniently obtained by condensing 2chlor0-5-nitrobenzoic acid and meta-phenylene diamine by the general procedure of the Ullman reaction.

Example 3 37 parts of B-acetamido-4-nitro-diphenylamine-Z-carboxylic acid is heated with 480 parts of sulphuric acid at 100 C. for 2 hours. The solution is cooled, 120 parts of water added and the heating continuedat 100 C. for a further /2 hour. 28 parts or 2-amino-7-nitroacridone is isolated in the same manner as described in the foregoing example.

The 3'-acetamido-4-nitro diphenylamine-zcarboXylic acid is .obtained by the acetylation of an aqueous solution of 3'--amino-4-nitro-diphenylamine-Z-carboxylic acid (obtained as described in Example 2) with acetic anhydride which readily afiords .3'-acetamido-4-nitro-diphenylamine-2-carboxylic acid M. Pt. 294 C.

What we claim is:

1. A process for the production of a 2.7-disubstituted acridone in which each of the substituents contains a nitrogen atom directly linked to a nuclear carbon atom which comprises heating a 3z4-disubstituted di-phenylamine-2 carboxylic acid of the general formula COQH R NH

COOH l in which .R isselected from the group consisting of amino, carboxyliccacylamido and nitro and R is selected from the group consisting of amino and carboxylic acylamido, with concentrated sulphuric acid for about one and a half to two hours at about 100 C.

4. A process .for the production of 2.7-diaminoacridone which comprises heating 3'-amino-4- acetamido diphenylamine-2-carboxy1ic acid with concentrated sulphuric acid.

5. The process of claim 4 .in which the reaction mixture is heated at about 100 C. for about two hours.

6. A process .for the production of 2-amino-7- nitroacridone whichcomprises heating 3-aminoei-wnitro-diphenylamine 2-- carboxylic acid with concentratedsulphuric acid.

7. The process of claim 6 in which the reaction mixture is heated at about 100 C. for about one anda halfehours.

8. A process for the production of 2-amino-'lnitroacridone which comprises heating 3'-acetamido-4-nitro-dipheny1amine-2 carboxylic acid with concentrated sulphuric acid.

9. The process of claim 8 in which the reaction mixture is heated at about 100 C. for about two hours.

ALAN AUGUST GOLDBERG. WILLIAM KELLY.

REFERENCES CITED 

3. A PROCESS FOR THE PRODUCTION OF A 2.7-DISUBSTITUTED ACRIDONE IN WHICH EACH OF THE SUBSTITUENTS CONTAINS A NITROGEN ATOM DIRECTLY LINKE TO A NUCLEAR CARBON ATOM WHICH COMPRISES HEATING A 3'':4-DISUBSTITUTED DIPHENYLAMINE - 2 - CARBOXYLIC ACID OF THE GENERAL FORMULA 